Inhibitors of Hepatitis C Virus

Abstract

Macrocyclic peptides are disclosed having the general formula: wherein R 3 , R 3 ′, R 4 , R 6 , R′, X, Q and W are described. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.

1 . A compound of formula I,  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:  
         (a) R 4  is hydrogen; C 1-6  alkyl; C 3-7  cycloalkyl; alkoxy; —C(O)—R 5 ; C(O)—N(R 5 ) 2 ; C(O)—OR 5 ; C 7-14  alkylaryl; or C 3-7  cycloalkyl, wherein the alkyl and the cycloalkyl are optionally substituted with halo; and wherein each R 5  is independently selected from C 1-9  alkyl, wherein the alkyl is optionally substituted with C 1-6  alkoxy, C 3-7  cycloalkoxy, halo-C 1-6  alkoxy, cyano, halo, hydroxy, amino, C 1-6  alkylamino, di (C 1-6 ) alkylamino, di(C 1-6 ) alkylamide, carboxyl, or (C 1-6 ) carboxyester;  
         (b) R 6  is hydrogen, C 1-6  alkyl, or C 3-7  cycloalkyl;  
         (c) R 3  and R 13  are each independently hydrogen or methyl;  
         (d) Q is a C 3-9  saturated or unsaturated chain wherein from 1 to 3 carbon atoms are independently replaced with an NR 8  group, wherein each NR 8  group is separated from another NR 8  group by at least one carbon atom in the chain; wherein R 8  is hydrogen; C 1-6  alkyl; C 1-6  cycloalkyl; —C(O)—R 9 , C(O)—OR 10 , C(O)—NR 11 R 12  or —SO 2 R 13 ; wherein the alkyl and the cycloalkyl are optionally substituted with halo, C 1-6  alkoxy, cyano or C 1-6  haloalkoxy; and wherein R 9 , R 11 , and R 12  are each independently hydrogen; C 1-6  alkyl or C 1-6  cycloalkyl, wherein the alkyl and the cycloalkyl are optionally substituted with halo, C 1-6  alkoxy, cyano or C 1-6  haloalkoxy; and wherein R 10  is C 1-6  alkyl or C 1-6  cycloalkyl, wherein the alkyl and the cycloalkyl are optionally substituted with halo, C 1-6  alkoxy, cyano or C 1-6  haloalkoxy; and wherein R 13  is aryl, C 1-6  alkyl or C 1-6  cycloalkyl, wherein the aryl, the alkyl, and the cycloalkyl are optionally substituted with halo, C 1-6  alkoxy, cyano or C 1-6  haloalkoxy;  
         (e) W is —NH—SO 2 —R 2 ; wherein R 2  is C 6-10  aryl, heterocyclyl or —NR b R c ; wherein R b  and R c  are each independently selected from the group consisting of hydrogen, C 1-7 alkoxy, C 1-7 alkyl, C 6-10  aryl, C 6-10  aryl(C 1-7 alkyl), C 1-7 cycloalkyl, C 1-7 cycloalkyl(C 1-7 alkyl), halo C 1-7 alkyl, heterocyclyl and heterocyclyl(C 1-7 alkyl);  
         (f) X is O, S, SO, SO 2 , OCH 2 , CH 2 O or NH;  
         (g) R′ is Het, C 6-10  aryl or C 7-14  alkylaryl, each optionally substituted with from one to five of the same or different R a  groups; or C 3-9  cycloalkyl or C 1-7  alkyl, wherein the cycloalkyl and the alkyl are optionally substituted with from one to five of the same or different members of the group consisting of halo, cyano, alkoxy, and dialkylamino;  
         provided that —XR′ is other than:  
         
           
             
             
                 
                 
             
           
         
         (h) R a  is C 1-6  alkyl, C 3-7  cycloalkyl, C 1-6  alkoxy, C 3-7  cycloalkoxy, halo-C 1-6  alkyl, CF 3 , mono- or di-halo-C 1-6  alkoxy, cyano, halo, thioalkyl, hydroxy, alkanoyl, NO 2 , SH, amino, C 1-6  alkylamino, di(C 1-6 ) alkylamino, di(C 1-6 ) alkylamide, carboxyl, (C 1-6 ) carboxyester, C 1-6  alkylsulfone, C 1-6  alkylsulfonamide, di (C 1-6 ) alkyl(alkoxy)amine, C 6-10  aryl, C 7-14  alkylaryl, or a 5-7 membered monocyclic heterocycle.  
       
     
     
         2 . The compound of  claim 1  wherein X is O.  
     
     
         3 . The compound of  claim 1  wherein R′ is Het.  
     
     
         4 . The compound of  claim 1  wherein R′ has a structure selected from:  
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         each optionally substituted with from one to five of the same or different R a  groups.  
       
     
     
         5 . The compound of  claim 1  wherein W is —NH—SO 2 —R 2 ; wherein R 2  is —NR b R c ; and R b  and R c  are each independently selected from the group consisting of hydrogen, C 1-7 alkoxy, C 1-7 alkyl, C 1-7 cycloalkyl, and C 1-7 cycloalkyl(C 1-7 alkyl).  
     
     
         6 . The compound of  claim 5  wherein R b  and R c  are each independently selected from the group consisting of hydrogen, C 1-7 alkoxy and C 1-7 alkyl.  
     
     
         7 . The compound of  claim 1  wherein Q is a C 5-7  saturated or unsaturated chain containing one to three NR 8  groups.  
     
     
         8 . The compound of  claim 1  where Q is unsaturated.  
     
     
         9 . The compound of  claim 1  where Q has the structure  
       
         
           
           
               
               
           
         
         wherein P is a C 3  saturated chain containing one NR 8  group, wherein R 8  is hydrogen; C 1-6  alkyl; or C 1-6  cycloalkyl, wherein the alkyl and the cycloalkyl are optionally substituted with halo, C 1-6  alkoxy, cyano or C 1-6  haloalkoxy; —C(O)—R 9 , C(O)—OR 10 , C(O)—NR 11 R 12  or —SO 2 R 13 ; R 9 , R 11 , and R 12  are each independently hydrogen; C 1-6  alkyl or C 1-6  cycloalkyl, wherein the alkyl and the cycloalkyl are optionally substituted with halo, C 1-6  alkoxy, cyano or C 1-6  haloalkoxy; R 10  is C 1-6  alkyl or C 1-6  cycloalkyl, wherein the alkyl and the cycloalkyl are optionally substituted with halo, C 1-6  alkoxy, cyano or C 1-6  haloalkoxy; R 13  is aryl, C 1-6  alkyl or C 1-6  cycloalkyl, wherein the aryl, the alkyl, and the alkyl are optionally substituted with halo, C 1-6  alkoxy, cyano or C 1-6  haloalkoxy.  
       
     
     
         10 . The compound of  claim 1  wherein R 4  is C(O)—OR 5 ; wherein R 5  is C 1-6  alkyl optionally substituted with halo, alkoxy, or cyano.  
     
     
         11 . The compound of  claim 10  wherein R 5  is C 1-6  alkyl optionally substituted with halo.  
     
     
         12 . The compound of  claim 1  wherein R 3  and R′ 3  are each hydrogen.  
     
     
         13 . A compound of formula II  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:  
         (a) R 4  is C(O)—OR 5 ; wherein R 5  is C 1-9  alkyl optionally substituted with C 1-6  alkoxy, cyano, or halo;  
         (b) Q is a C 5-7  saturated or unsaturated chain wherein one carbon atom is replaced with an NR 8  group; R 8  is C 1-6  cycloalkyl, optionally substituted with halo, C 1-6  alkoxy, cyano or C 1-6  haloalkoxy;  
         (c) W is —NH—SO 2 —R 2 ; wherein R 2  is C 6-10  aryl, heterocyclyl or —NR b R c ; wherein R b  and R c  are each independently selected from the group consisting of hydrogen, C 1-7 alkoxy, C 1-7 alkyl, C 6-10  aryl, C 6-10  aryl(C 1-7 alkyl), C 1-7 cycloalkyl, C 1-7 cycloalkyl(C 1-7 alkyl), halo C 1-7 alkyl, heterocyclyl and heterocyclyl(C 1-7 alkyl);  
         (d) X is O;  
         (e) R′ is Het, C 6-10  aryl or C 7-14  alkylaryl, each optionally substituted with from one to five of the same or different R a  groups; or C 3-9  cycloalkyl or C 1-7  alkyl, each optionally substituted with from one to five of the same or different members of the group consisting of halo, cyano, alkoxy and dialkylamino;  
         provided that —XR′ is other than:  
         
           
             
             
                 
                 
             
           
         
         (f) R a  is selected from the group consisting of C 1-6  alkyl, C 3-7  cycloalkyl, C 1-6  alkoxy, C 3-7  cycloalkoxy, halo-C 1-6  alkyl, CF 3 , halo-C 1-6  alkoxy, cyano, halo, thioalkyl, hydroxy, amino, C 1-6  alkylamino, di(C 1-6 ) alkylamino, di(C 1-6 ) alkylamide, carboxyl, (C 1-6 ) carboxyester, C 1-6  alkylsulfone, C 1-6  alkylsulfonamide, di (C 1-6 ) alkyl(alkoxy)amine, C 6-10  aryl, C 7-14  alkylaryl and a 5-7 membered monocyclic heterocycle.  
       
     
     
         14 . A composition comprising the compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.  
     
     
         15 . The composition of  claim 14  further comprising at least one additional compound having anti-HCV activity.  
     
     
         16 . The composition of  claim 15  wherein at least one of the additional compounds is an interferon or a ribavirin.  
     
     
         17 . The composition of  claim 16  wherein the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastiod interferon tau.  
     
     
         18 . The composition of  claim 15  wherein at least one of the additional compounds is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5′-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.  
     
     
         19 . The composition of  claim 15  wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment of an HCV infection.  
     
     
         20 . A method of treating an HCV infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof.  
     
     
         21 . The method of  claim 20  further comprising administering at least one additional compounds having anti-HCV activity prior to, after, or simultaneously with the compound of  claim 1 , or a pharmaceutically acceptable salt thereof.  
     
     
         22 . The method of  claim 21  wherein at least one of the additional compounds is an interferon or a ribavirin.  
     
     
         23 . The method of  claim 22  wherein the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastiod interferon tau.  
     
     
         24 . The method of  claim 21  wherein at least one of the additional compounds is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5′-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.  
     
     
         25 . The method of  claim 21  wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment of an HCV infection.